Borna Disease: a Possible Emerging Zoonosis Jean-Marc Boucher, Eric Barbillon, Florence Cliquet

Borna disease: a possible emerging zoonosis Jean-Marc Boucher, Eric Barbillon, Florence Cliquet

To cite this version:

Jean-Marc Boucher, Eric Barbillon, Florence Cliquet. Borna disease: a possible emerging zoonosis. Veterinary Research, BioMed Central, 1999, 30 (6), pp.549-557. hal-00902595

HAL Id: hal-00902595 https://hal.archives-ouvertes.fr/hal-00902595 Submitted on 1 Jan 1999

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Borna disease: a possible emerging zoonosis

Jean-Marc Boucher Eric Barbillon Florence Cliquet

Laboratoire d’études sur la rage et la pathologie des animaux sauvages, AFSSA Nancy, B.P. 9, 54220 Malzéville, France

(Received 6 May 1999; accepted 26 August 1999)

Abstract - The Borna disease virus (BDV) causes a disease of the central nervous system (CNS) in several vertebrate species. The progress made over the last 30 years in molecular biology has allowed us to identify the unique characteristics of the virus, such as its persistence in the CNS and the way it is expressed. This has allowcd scientists to classify this pathogenic agent in a new family of RNA viruses. BDV affects a very large spectrum of hosts and is responsible for a disease characterised by behavioural anomalics. The large range of intra- or inter-specific symptoms of this disease (from persistence of the virus without clinical symptoms to CNS destruction) make epidemiological studies very difficult. Different diagnostic tools have allowed the detection of this infectious agent in different species around the world (central Europe, USA, UK, Japan, Iran, etc.). The disease can be fatal for sheep and horses (its primary natural hosts) and can infect other species such as rats, cattle, dogs, cats or pigeons. In human beings, BDV could be responsible for certain psychiatric disorders. In France, the limited number of epidemiological studies that have been conducted up until now (in veterinary and medical fields) does not allow scientists W ascertain whether the disease is present in France or not. Due to the suspected large gcographical distribution of this infectious agent, however, we could expect the presence of BDV in France. O ltira/Elsevier, Paris.

Borna disease virus / molecular structure / transmission / pathology / epidemiology

Résumé - La maladie de Borna : une possible zoonose émergente. Le virus de la maladie de Borna (BDV : Borna disease virus) est l’agent étiologique d’une maladie touchant le système nerveux central (SNC) de diverses espèces. Les progrès réalisés depuis une trentaine d’années en biologie molé- culaire ont permis de mettre en évidence des caractéristiques uniques du virus, à savoir : sa persistance dans le SNC et son mode d’expression. Celui-ci a permis de classer cet agent pathogène dans une nou- velle famillc de virus à ARN. Cet agent infecticux qui se caractérise par un spectre d’hôtes très large, provoque une maladie se traduisant par divers troubles comportementaux, et par des symptômes inter et intra-specifiques aussi divers que variés pouvant aller de la persistance virale sans symp- tômes apparents jusqu’à la destruction du SNC aboutissant à la mort de l’animal. Ces caractéris- tiques rendent l’étude épidémiologique de cette maladie très difficile. Divers outila de diagnostic

* Correspondence and reprints Tel.: (33) 3 83 29 89 50; fax (33) 3 83 29 89 59; c-mail: biologie.ly,,,,savirus(a-)nancy.afssa.f’r ont été mis au point et ont déjà permis de mettre en évidence le virus chez ses différents hôtes à tra- vers le monde (Europe centrale, Royaume-Uni, États-Unis, Japon, Irati, etc.). Il peut être mortel pour les moutons et les chevaux et inlectc de nombreuses autres espèces. Chez l’homme, le virus pour- rait être la cause de certains désordres psychiatriques. En France, le peu d’études qui ont été réalisées (aussi bien dans le domaine vétérinaire que chez l’homme) ne permettent pas d’affirmer la présence du virus dans l’hexagonc. Cependant, étant donné l’étendue géographique actuellement connue de ce virus, il serait intéressant autant du point de vue scientifique que du poinl de vue de la santé publique de se pencher sur l’éventuelle présence du virus chez ses différents hôtes en France. © InraElsevicr, Paris. virus de Borna / structure / transmission / pathologie / épidémiologie

1. INTRODUCTION In France, the disease is very poorly known; it was studied in our country until Borna disease is a viral disease known the 1940s, then the replacement of horses to man for the last two centuries. At the end by motor vehicles in agriculture and in the of the l9th century, in Saxe (Germany: the army progressively ended all research. Much town of Borna and neighbouring towns), it progress, from a molecular point of view, has been made since the 1970s: at this provoked an epidemic among horses of the only cavalry. Since then, it has been identified time scientists observed that the infected in different countries: Germany, Switzer- cells expressed specific proteins on their land [40], Austria [55 the United States surface (both 40- and 24-kDa proteins are used for immuno- [201, Japan [17], Iran [1], Israel and more currently diagnosis by recently in the United Kingdom 1391. transfer of proteins (western blot)). In 1977, According to the literature, its geographic the structure of the capsid (icosahedral) as well as the characteristics of the of distribution is probably much more genome widespread [18]. the virus (an RNA virus) were discovered. The vector(s) and the reservoir(s) of the The results of the research performed disease have not yet been identified and the during the 1980s and 1990s have suggested common pathways of intraspecific and inter- that Borna disease is present in many dif- specific transmission are unknown, in both ferent regions around the world, even though its natural hosts and in its experimental the most recognised form of the disease hosts. appears principally in specific regions of Germany and Switzerland. The Borna virus gaviral order, it is highly glycosylated. has, for a long time, been considered as an D-galactose, D-mannose as well as D- epizootic infectious agent until serological glucosamine and D-galactosamine (under studies in the 1980s formulated the hypoth- the N-acetylated form) are its principal esis of a possible human contamination. monosaccharides [22!. These residues are usually bound to serine and asparagine, but also to tyrosine, leucine 2. THE BORNA VIRUS and isoleucine. The role of this glycoprotein has not yet been determined, but 2.1. Virion structure [23] the structure of this matrix protein has been found in certain viral families such BDV is a symmetrical icosahcdral as the coronaviruses [22[. Finally, this enveloped virus with a diameter ranging glycoprotein is the only molecule on the from 100 to 130 nm. surface of the virion which induces neu- Treatment of infected cell lines (MDCK) tralising antibody (Ab) production [22]. by butyrate has permitted the visualisation - The envelope protein (P56) exists as two and observation of viral particles by elec- forms in the infected tissues: a strongly tron microscopy. glycosylated complete 84-kDa form and a 43-kDa form from The virion is made up of a 7-nm-wide incomplete resulting the of the form spherical envelope with a crescent-shaped hydrolysis complete by a from the host cells internal structure and includes a 4-nm-wide protease (furine) GP43 is found on the surface nucleocapsid. This structure is similar to [ )4j. Only of the virion where it has an essential role that of the Rhabdoviruses and has the par- ticularity of being associated with small in the mechanism of fusion between the viral and the cellular membrane incomplete viral particles. One may note envelope that the reconstitution of the virion before [ !4). This protein also possesses the par- the bud- budding occurs on the cell surface, whereas ticularity of partially inhibiting of the virus outside of its host’s cell replication and transcription occur in the ding nucleus of the infected cells [31. after infection [27]. - The viral polymerase (RNA dependent) 2.2. Proteinic structures of the virus is the largest protein produced by the virus (approximately 180 kDa). It has BDV is made up of the following five several characteristics in common with major proteins. those produced by other negative and

- The nucleoprotein (P40) has two iso- non-segmented RNA viruses (NNS forms of 38 and 39 kDa, and is the infec- RNA) [3]. This protein has not, however, been detected and its tious protein the most abundantly pro- experimentally has not been discovered. duced by the virus and possesses an activity yet important immunogenic power [36, 371. 2.3. and

- Replication transcription The phosphoprotein (P24) is also strongly In its immunogenic. transcriptional unit, Borna virus infections are characterised it has another a reading phase producing by a non-cytolytic replication strategy [19] 10-kDa that is found in infected protein and by a very small concentration of extra- cells but whose role is not known [52, yet cellular virus. Only the nervous cells are 54]. sensitive to the virus. One of the particular- - The BDV matrix protein is an 18-kDa ities of this single-stranded NNS RNA virus molecule. In contrast to the matrix pro- [6, 26! is that it replicates inside the nucleus teins of other viruses of the Monone- of infected cells [6]. Native viral RNA is bound to proteins in order to form ribonu- necessary to define a new taxon of the cleoproteins (RNP). The RNP, in contrast Mononegaviral order: the Bornaviridae [8]. to free RNA, are infectious [38]. They allow viral RNA to be cellular protected against 2.5. Borna virus transmission nucleases and are for the indispensable syn- and thesis of viral macromolecules as well as pathogenesis for viral RNA replication [7]. The RNP are therefore transcribed in the nuclei of infected It seems that BDV transmission occurs cells by cellular mechanisms. The comple- by nasal and buccal (saliva) secretions and The virus infects the mentary RNA produced then serves as the orally (aerosols) [43]. nerve of the matrix for both the replication and the pro- endings olfactory epithelium, duction of viral proteins. and migrates intra-axonally to the central nervous system (CNS) [4] where it creates One may remark that the viral genome lesions manifested by the loss of white mat- seems to be stable because the total ter along the blood vessels, as well as by sequences [3, 7, 9] established up until now the appearance of astrocytes [5]. Its distri- on infected rat isolates, on cell lines (oligo- bution in the CNS makes one think that the dendrocytes and C6 cells) as well as on virus possesses a preferential tactism for the peripheral blood cells (PBMC) show more limbic system. In addition, its stratified dis- than 95 % similarity. tribution in the CNS (notably in the hip- pocampus) covers zones where certain neu- roreceptors are present and 2.4. Genome structure (glutamate dopamine among others) [15, 35]. This has helped formulate the hypothesis that these The development of infected cell lines receptors play an important role in the pro- as well as the progress made in molecular gression of the viral infection in cerebral genetics have permitted researchers to bet- tissue [15]. ter understand the functioning of BDV: the After having reached the CNS, where the genome is 8.9 kb long and composed of two virus disturbs the of several neu- major coding sequences as well as several functioning rotransmitter systems [25, 35], the infection complementary non-coding sequences. The continues to diffuse the intra-axonal path- genome may be divided into three groups by way, towards the nervous of genes: the first encodes the P40 and P24 peripheral system where it infects the nerves of different proteins (nucleoprotein and phosphoprotein and can then be excreted natural cofactor of the viral the second organs by polymerase); secretions. Viral RNA has been identified encodes the viral (P166 envelope proteins in mononuclear cells of blood and P56) and the last encodes the viral poly- peripheral (in humans [45] and in rats [44]), but this infec- merase [7]. The organisation of the genome, tion remains minor as it affects one as well as the structure of this virus are sim- only cell out of 5.106 ilar to those of the Mononegaviral viruses approximately [44]. (the order includes the Filoviridae (Marburg From an immunological point of view, and Ebola viruses), the Paramyxoviridae the cellular-mediated immune response and (mumps and measles) and the Rhabdoviri- notably the CD8+ T lymphocytes (cyto- dae (rabies)). Because of the small size of its toxic) play a central role in the formation genome, however, this virus must accumu- of CNS lesions [50]. In fact, the infected late different specific strategies in the way it nervous cells express and present molecules is expressed (overlapping of transcriptional of the major histocompatibility complex units and of reading phases [54], splicing (MHCI) on their surface. These molecules of specific RNAm [47]), which makes it a are bound to viral peptides (principally epi- unique virus. These characteristics made it topes issued from the P40 molecule and, to a lesser extent, epitopes from the envelope [1, 17, 21, 24, 48, 56]. The western blot [1, protein GP 84 [36]) that the nervous cells 10, 12, 17, 21, 34] and indirect immunoflu- do not produce when they are healthy. These orescence techniques [2, 4, 10, 20, 28] based molecules of the MHCI induce lysis of on the detection of anti-BV Ab, as well as infected neurons by CD8+ lymphocytes the RT-PCR technique using PBMC, can which enter in a peri-vascular way into the be performed using simple blood samples infected zone. These lymphocytes provoke which allow the treatment of a large number much more serious lesions than those caused of samples without killing the animals. This by BDV itself. This phenomenon explains is, therefore, an advantage for epidemio- the lack of symptoms in immunodepressed logical studies. The results obtained by serol- animal subjects [51].]. ogy or by RT-PCR may, however, be criti- Concerning the humoral-mediated cised: the identification of antibodies in a serum is not able to be correlated immune response, the specific viral anti- directly with an because cases of bodies do not protect and do not prohibit infection, many without infection nor limit the replication of the virus whose seropositivity apparent localisation principally remains intracellular have been described (notably in horses [20, [16]. 431). The hypothesis of the possible exis- tence of cross-reactions with other antigens than those of the Borna virus has been sug- The 3. EPIDEMIOLOGICAL DATA gested [20]. serological methodologies used by different laboratories may have 3.1. Epidemiological tools important variations which may be responsible for non-reliable results [18, 48]. The The study of the prevalence of this dis- RT-PCR technique is very sensitive and therefore controversial results because ease is apprehended by the search for spe- gives cific antibodies and/or by the isolation of of a non-negligible risk of false-positive the infectious agent. To date, five principal results [13, 18, 24, 42]. techniques have been described in the liter- In any case, even if the techniques cited ature: immunohistochemistry, histology, the above are perfectly mastered, an epidemio- reverse transcriptase-polymerase chain reac- logical study amongst natural animal popu- tion (RT-PCR), protein immunotransfer lations could only be performed using sev- methods (western blot) and indirect eral diagnostic methods owing to the immunofluorescence. These different tech- absence of a correlation between the pres- niques each have different advantages from ence of specific antibodies and that of viral both practical and epidemiological points RNA[)3,34). of view.

Histology, which is based on the direct observation of cerebral lesions [5, 28, 30], as 3.2. Borna virus and animal health well as immunohistochemistry, which neces- sitates cell smears [ 10, 28], are techniques The Borna virus causes a disease of the that use sections of cerebral tissues. These central nervous system which animals man- two techniques allow for an infallible diag- ifest via profound abnormal behaviour. The nosis, but they can only be performed after clinical signs depend on the animal species, the death of an animal, therefore explain- the age and immunological status of the ani- ing why they cannot be adapted to large mal, the strain of the virus and the pathway scale epidemiological studies. The RT-PCR of infection. Both natural and experimental technique is used to detect isolated viral characteristic signs of the disease are gen- RNA from brain cells [10, 46] or from erally excitability and hyperactivity or apa- peripheral blood mononuclear cells (PBMC) thy followed by paralysis, which may evoke symptoms of rabies. The first naturally ent species (sheep, horses and dogs) for infected species described in the literature which, by western blot analysis, we showed were horses and sheep; however, other the presence of anti-P40 and anti-P24 anti- species may be infected naturally: cattle, bodies in serum from a sheep; however, ostrich, lamas, deer, goats, rabbits [33, 43] these results need to be confirmed by other and cats [28, 39]. Some studies have shown existing techniques. A recent study [ 17] car- that certain species were resistant to BDV ried out in Japan on healthy sheep showed a infections (ferret [3 1 ], Syrian hamster [29] prevalence greater than 36 %. and In horses and dur- pigeon [57]). sheep, To date, no case (either human or ani- ing the acute phase of the illness, the virus mal) has been detected in France, but it is causes non-purulent meningo-encepha- possible to explain this situation by the lack lomyelitis. of studies on this disease carried out in our In infected sheep, mortality is higher than country. 50 % [43]. Certain studies, however, have shown seropositivity without any apparent symptoms [ 17]. The death rate of horses is 3.3. Vector(s) and reservoirs(s) between 80 and 100 % [43] with low seropositivities. But asymptomatic infec- Several hypotheses have been proposed tions are also common in horses. Indeed, concerning the vectors and reservoirs: prevalences of serum antibodies between according to most scientists, rodents may 30 and 50 % have been observed in horses be both the vectors and reservoirs [18, 43]; without any apparent symptoms [20, 431 for others, horses, domestic carnivores (cats and the virus may persist for 5 years without in particular), cattle and insects may be the any visible symptoms in its host [43]. vectors [ 18, 43]. The peak of incidence of the disease seems to be situated between the For the first time in 1998, and in contra- beginning of the spring and the beginning of diction with data published by Zwick et al. the summer [11]; this period coincides with [57] in which dogs were considered as a that of the activity of insects, who might be resistant species, a dog euthanised because the vectors [43]. But to date, no data allow of rabies suspicion was declared infected us to confirm one or the other of these by BDV by a group of Austrian researchers [55]. The experimental infection of the dog hypotheses. had already been reported in 1930 by Nico- lau and Galloway [32], but this was the first 3.4. The Borna virus and public health case observed of a dog infected naturally. This discovery has reinforced the idea that Cases of infection by the Borna virus BDV infections do not depend only on have been diagnosed in Germany in several species, but also on other factors such as animal and less than individuals. More the disease was species (horses sheep), recently, 50 km from the French border. We diagnosed in domestic cats in the UK [39]. may, therefore, question whether the disease is Rodents (in particular the rat, which is present in our country. the best model) [4, 30, 49], cattle, donkeys, The first studies made on humans are and birds be dogs, macaques may experi- based on data. Borna infected different serological Specific mentally by pathways virus antibodies were detected for the first (intracerebral, intraneuronal, intraperitoneal, time in a from and subcutaneous and patient suffering epilepsy intranasal) [15]. psychological problems in 1976 (Ludwig Recently, we carried out an epidemio- and Koprowski, unpublished results). But logical study in north-east France (non-pub- this case was strengthened only 10 years lished results) on healthy animals of differ- later when a group of patients suffering from psychiatric disorders were found to have 4. CONCLUSION antibody prevalences between 5 and 15 % [ 121. Other sero-epidemiological studies [2, The unique characteristics of the Borna 40-42, 53] have shown the presence of spe- disease virus (persistence in the CNS, ways cific anti-BDV antibodies in subjects with of expression, large spectrum of hosts, etc.) neurological or psychiatric troubles. The and its large scale of symptoms make the presence of viral RNA detected by RT-PCR study of Borna disease very difficult. There- was shown in monocytes of 40-50 % of the fore, much effort must be made to extend subjects affected by acute or chronic psy- knowledge of this single-stranded NNS chiatric syndromes [46]. In a study carried RNA virus. out in Japan, viral RNA was detected in 5 °lo The neuropathology of BDV-infected of volunteer blood donors 21 ]. In 1996, the animals is better understood: much progress virus was detected in the brain of a patient has been made recently in the comprehen- affected by neuropsychiatric disorders 10] sion of the formation of the lesions [48, SOJ; (in addition to the identification of specific however, many questions remain concerning antibodies and viral RNA). the mechanisms of immune response [48!.[. Moreover, it is absolutely necessary that More recently, using RT-PCR, a research laboratories who study this virus standard- group [45] showed the presence of the virus ise their diagnostic methods [48 notably in the brains of nine out of 17 analysed with regard to the molecular biology meth- affected with and in patients schizophrenia ods (RT-PCR), which are highly sensitive, two out of five patients affected with a bipo- and the immunological methods (western lar disorder. blot, indirect immunofluorescence assay), which may not be specific enough. These The results, however, remain controver- methods are, however, at this time the only sial. From inter-laboratory studies carried way of the Borna disease virus in out in and in it has diagnosing Germany Japan [48], living beings. emerged that the techniques used (RT-PCR, In fact, at this time, it seems that search- in particular) are not standardised. RT-PCR for antibodies and/or viral RNA [24, 42] may furnish false-positive results, ing specific is not sufficient to ascertain the of which are probably due to contamination of presence the virus inside its host. Therefore, the amplified genetic material. In this con- diag- nostic tools must be to allow text, even though traces of the virus were improved epi- studies on human or animal detected (in one brain [10] by isolation of demiological the virus), the relationship between the infec- populations. tion by BDV and the psychiatric symptoms cannot be outwardly accepted; in order for REFERENCES this to be other stud- relationship accepted, ! Bahmani M.K., Nowrouzian I., Nakaya T., Naka- ies based on detection methods are adequate mura Y., Hagiwara K., Takahashi H., Rad M.A., necessary. 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